PROJECT 3: ABSTRACT CD4 T cells play a key role orchestrating the immune response and play an important role controlling and eliminating viral infections. Due to HIV-1 tropism for CD4 T cells and especially HIV-1 specific CD4 T cells, the CD4 T cell response to combat HIV-1 infection is compromised. The underlying goal of this project is to develop a strategy that would restore full CD4 T cell activity to fight against HIV-1 infection. Working with Project 2, we will employ the most effective way to protect CD4 T cells from HIV-1 infection. Next, we will examine which CD4 T cell subset and which chimeric antigen receptor best restores durable HIV-1 specific activity to CD4 T cells. We will work closely with Project 4 to define the key factors that control the durably and functionality of CD4 T cells. Then using this information we will further refine our gene engineering strategy to enhance anti-HIV-1 CD4 T cell activity. In aim 3 we will model adoptive T cell trials using humanized mice to determine which combination of engineered provide the most effective and durable control of HIV-1 replication. These studies will provide the basis and rationale for a clinical trial that will follow the study described in Project 1. SA1: To identify the optimal CD4 CAR costimulatory domain and cell type to give durable control of HIV-1 infection in vitro. SA2: To identify the optimal CD4 CAR costimulatory domain and cell type that provides the most help to HIV-1 specific CD8 T cells. SA3: To investigate whether protected HIV-1 specific T cells can functionally control HIV-1 replication in vivo. .